The difficulty of bringing pharmaceutical substances with problematic bioavailability into a satisfactory pharmaceutically administerable form is generally known. With several drugs, absorption may be as little as 30%, or less, of the orally administered dose when administered in a conventional dosage form, i.e., when no special mechanism is used to enhance absorption of the drug. In addition, poorly adsorbed drugs often display large inter- and intra-subject variability in bioavailability. See Aungst, B. J., J. Pharm. Sci., 82:979-987, 1993. Specific examples (with the average bioavailability given in parentheses) include methyldopa (25%) with a range of 8% to 62%; and nalbuphine (approximately 17%) with a range of 6% to 40%.
The absorption of most drugs depends on two processes: (1) the dissolution of the drug in physiological fluids and (2) the absorption process itself, i.e., the process by which a drug in solution enters the cells at the absorption site and, finally enters general circulation. Many drugs are adsorbed by passive diffusion, i.e., a spontaneous migration of drug molecules from a region of high concentration to a region of low concentration. Other drugs are adsorbed by facilitated or active transport which involve the expenditure of energy by the body. In either event, the dissolution of the drug is the first step in the absorption process unless the drug is administered as a solution. On the other hand, some drugs are adsorbed by the process of pynocytosis or endocytosis which involve the engulfing of solid particles and the incorporation of such particles into the cellular contents.
To compensate for the poor adsorption displayed by many drugs, a pharmaceutical formulation may utilize one or more mechanisms to increase the extent to which the administered drug is adsorbed. While there are a vast number of such techniques, these techniques may be grouped into the following broad categories: (1) enhancement of the rate or extent of dissolution; (2) facilitation of an absorption process that would have occurred naturally; and (3) inducement of an absorption mechanism that would not naturally have occurred or which would have occurred to an insignificant extent. Thus, incorporation of a chemical substance that opens tight junctions in order to increase the rate of absorption of a drug that would normally have been adsorbed slowly through the paracellular route is an example of the second technique. On the other hand, incorporation of a drug within oil droplets for the purpose of involving the lymphatic system in the absorption of the drug (where this would not, otherwise, have occurred) is an example of the third technique.
More recently, powdered solution technology has been proposed as a technique for the delivery of water-insoluble drugs. See Spireas et al., "Powdered Solution Technology: Principles and Mechanisms, Pharm. Research, Vol. 9, No. 10 (1992) and Sheth, A. and Jarowski, C. I., "Use Of Powdered Solutions To Improve The Dissolution Rate Of Polythiazide Tablets," Drug Development and Industrial Pharmacy, 16(5), 769-777 (1990). The concept of powdered solutions involves converting drug solutions or liquid drugs into a dry, nonadherent, free-flowing compressible powder by admixing the liquid drugs or drug solutions with a selected carrier. Although the drug is in a solid form, it is held in a solubilized liquid state, which increases the wetting properties of the drug, and therefore enhances the dissolution. Unfortunately, the application of powder solution technology has been limited because the resulting admixture powder generally has poor and erratic flowability and compressibility properties.